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We describe robust chemical approaches toward putative CCR5 scaffolds designed in our laboratories. Evaluation of analogues in the 125I-[MIP-1β] binding and Ba-L-HOS antiviral assays resulted in the discovery of 64and 68in the 4,4-disubstitited piperidine class H, both potent CCR5 ligands (pIC 50= 8.30 and 9.00, respectively) and HIV-1 inhibitors (pIC 50= 7.80 and 7.84, respectively, in Ba-L-HOS assay). In addition, 64and 68were bioavailable in rodents, establishing them as lead molecules for further optimization toward CCR5 clinical candidates. [ABSTRACT FROM AUTHOR]